Determining the effects of Candida utilis-fermented pea starch vs. unfermented pea starch, alone or in whole diets, on palatability and glycemic response in dogs and cats.

Current research suggests yeast fermentation has the potential to improve palatability of pea-based diets for both cats and dogs. However, to be useful, fermentation should not compromise other healthy attributes of peas such as a low glycemic response. Fermentation of uncooked pea starch with Candida utilis (ATCC 9950) appeared to increase crude protein, crude fiber content, inorganic compounds (phosphorus and iron) and phenols. Whole diets were designed with fermented and unfermented pea starch to assess palatability, food intake, and glycemic responses in unacclimated, mixed sex Beagle dogs and mixed breed cats (n = 8 and n = 7, respectively). For palatability testing, a control diet was formulated with 30% corn starch as well as test diets with 30% inclusion of fermented or unfermented pea starch (all lab-made), then compared to a commercial diet containing pea starch (Legacy/Horizon). Fermentation had little effect on rapidly digestible starch either in uncooked starch form or when incorporated into whole diets, but did decrease resistant starch by 15% and increase slowly digestible starch by 20%. Palatability tests using either two choices or four choices at a time revealed a significant preference for the fermented pea starch diet (p < 0.01) in both species. For the glycemic responses, a total of four different pea products were included: unfermented pea starch, fermented pea starch, and 30% inclusion of unfermented and fermented pea starch in whole formulated diets. There were no significant changes in glycemic responses with the fermented pea diet compared to the unfermented diet, demonstrating that healthful low glycemic properties of pea starch were retained after C. utilis fermentation. Overall, C. utilis-fermentation technique was successfully adapted to pea starch where it resulted in increased palatability and food intake in dogs and cats, with potential to positively contribute to overall health benefits for both species.

Rare structural variants, aneuploidies, and mosaicism in individuals with Mullerian aplasia detected by optical genome mapping.

The molecular basis of Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome remains largely unknown. Pathogenic variants in WNT4 and HNF1B have been confirmed in a small percent of individuals. A variety of copy number variants have been reported, but causal gene(s) remain to be identified. We hypothesized that rare structural variants (SVs) would be present in some individuals with MRKH, which could explain the genetic basis of the syndrome. Large molecular weight DNA was extracted from lymphoblastoid cells from 87 individuals with MRKH and available parents. Optical genome mapping (OGM) was performed to identify SVs, which were confirmed by another method (quantitative PCR, chromosomal microarray, karyotype, or fluorescent in situ hybridization) when possible. Thirty-four SVs that overlapped coding regions of genes with potential involvement in MRKH were identified, 14 of which were confirmed by a second method. These 14 SVs were present in 17/87 (19.5%) of probands with MRKH and included seven deletions, three duplications, one new translocation in 5/50 cells-t(7;14)(q32;q32), confirmation of a previously identified translocation-t(3;16)(p22.3;p13.3), and two aneuploidies. Of interest, three cases of mosaicism (3.4% of probands) were identified-25% mosaicism for trisomy 12, 45,X(75%)/46,XX (25%), and 10% mosaicism for a 7;14 translocation. Our study constitutes the first systematic investigation of SVs by OGM in individuals with MRKH. We propose that OGM is a promising method that enables a comprehensive investigation of a variety of SVs in a single assay including cryptic translocations and mosaic aneuploidies. These observations suggest that mosaicism could play a role in the genesis of MRKH.

A crosswalk of foundational BSN population health documents and the AACN essentials.

To guide the development of entry-level nursing education, the American Association of Colleges of Nursing (AACN) published the Essentials document in 2021 with a broadened scope of competencies. Community, population, and public health (CPPH) nurse educators use a number of foundational documents to crosswalk for gaps in the AACN principles, highlighting the need of including these contemporary documents within the baccalaureate CPPH nursing curriculum. In this crosswalk, the authors highlight important capabilities and knowledge exclusive to these fundamental documents and tools, as well as the relevance of these competencies and knowledge to CPPH baccalaureate nursing education.

Maternal and newborn health for the urban poor: the need for a new mental model and implementation strategies to accelerate progress.

BACKGROUND: Urbanization challenges the assumptions that have traditionally influenced maternal and newborn health (MNH) programs. This landscaping outlines how current mental models for MNH programs have fallen short for urban slum populations and identifies implications for the global community. We employed a three-pronged approach, including a literature review, key informant interviews with global- and national-level experts, and a case study in Bangladesh. MAIN BODY: Our findings highlight that the current mental model for MNH is inadequate to address the needs of the urban poor. Implementation challenges have arisen from using traditional methods that are not well adapted to traits inherent in slum settings. A re-thinking of implementation strategies will also need to consider a paucity of available routine data, lack of formal coordination between stakeholders and providers, and challenging municipal government structures. Innovative approaches, including with communications, outreach, and technology, will be necessary to move beyond traditional rural-centric approaches to MNH. As populations continue to urbanize, common slum dynamics will challenge conventional strategies for health service delivery. In addition, the COVID-19 pandemic has exposed weaknesses in a system that requires intersectoral collaborations to deliver quality care. CONCLUSION: Programs will need to be iterative and adaptive, reflective of sociodemographic features. Integrating the social determinants of health into evaluations, using participatory human-centered design processes, and innovative public-private partnerships may prove beneficial in slum settings. But a willingness to rethink the roles of all actors within the delivery system overall may be needed most.

Altered cerebrovascular regulation in low birthweight swine.

Full-term low birthweight (LBW) offspring exhibit peripheral vascular dysfunction in the postnatal period; however, whether such impairments extend to the cerebrovasculature remains to be elucidated. We used a swine model to test the hypothesis that LBW offspring would exhibit cerebrovascular dysfunction at later stages of life. Offspring from 14 sows were identified as normal birthweight (NBW) or LBW and were assessed at 28 (similar to end of infancy) and 56 (similar to childhood) days of age. LBW swine had lower absolute brain mass, but demonstrated evidence of brain sparing (increased brain mass scaled to body mass) at 56 days of age. The cerebral pulsatility index, based on transcranial Doppler, was increased in LBW swine. Moreover, arterial myography of isolated cerebral arteries revealed impaired vasoreactivity to bradykinin and reduced contribution of nitric oxide (NO) to vasorelaxation in the LBW swine. Immunoblotting demonstrated a lower ratio of phosphorylated-to-total endothelial NO synthase in LBW offspring. This impairment in NO signaling was greater at 28 vs. 56 days of age. Vasomotor responses to sodium nitroprusside (NO-donor) were unaltered, while Leu31, Pro34 neuropeptide Y-induced vasoconstriction was enhanced in LBW swine. Increases in total Y1 receptor protein content in the LBW group were not significant. In summary, LBW offspring displayed signs of cerebrovascular dysfunction at 28 and 56 days of age, evidenced by altered cerebral hemodynamics (reflective of increased impedance) coupled with endothelial dysfunction and altered vasomotor control. Overall, the data reveal that normal variance in birthweight of full-term offspring can influence cerebrovascular function later in life.

Hyperglycemia and Adverse Pregnancy Outcome Follow-Up Study: newborn anthropometrics and childhood glucose metabolism.

AIMS/HYPOTHESIS: We aimed to examine associations of newborn anthropometric measures with childhood glucose metabolism with the hypothesis that greater newborn birthweight, adiposity and cord C-peptide are associated with higher childhood glucose levels and lower insulin sensitivity. METHODS: Data from the international, multi-ethnic, population-based Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study and the HAPO Follow-Up Study were used. The analytic cohort included 4155 children (mean age [SD], 11.4 [1.2] years; 51.0% male). Multiple linear regression was used to examine associations of primary predictors, birthweight, newborn sum of skinfolds (SSF) and cord C-peptide, from HAPO with continuous child glucose outcomes from the HAPO Follow-Up Study. RESULTS: In an initial model that included family history of diabetes and maternal BMI during pregnancy, birthweight and SSF demonstrated a significant, inverse association with 30 min and 1 h plasma glucose levels. In the primary model, which included further adjustment for maternal sum of glucose z scores from an oral glucose tolerance test during pregnancy, the associations were strengthened, and birthweight and SSF were inversely associated with fasting, 30 min, 1 h and 2 h plasma glucose levels. Birthweight and SSF were also associated with higher insulin sensitivity (Matsuda index) (ß = 1.388; 95% CI 0.870, 1.906; p < 0.001; ß = 0.792; 95% CI 0.340, 1.244; p < 0.001, for birthweight and SSF higher by 1 SD, respectively) in the primary model, while SSF, but not birthweight, was positively associated with the disposition index, a measure of beta cell compensation for insulin resistance (ß = 0.034; 95% CI 0.012, 0.056; p = 0.002). Cord C-peptide levels were inversely associated with Matsuda index (ß = -0.746; 95% CI -1.188, -0.304; p < 0.001 for cord C-peptide higher by 1 SD) in the primary model. CONCLUSIONS/INTERPRETATION: This study demonstrates that higher birthweight and SSF are associated with greater childhood insulin sensitivity and lower glucose levels following a glucose load, associations that were further strengthened after adjustment for maternal glucose levels during pregnancy. Graphical abstract.

Genetics of agenesis/hypoplasia of the uterus and vagina: narrowing down the number of candidate genes for Mayer-Rokitansky-Küster-Hauser Syndrome.

PURPOSE: Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome consists of congenital absence of the uterus and vagina and is often associated with renal, skeletal, cardiac, and auditory defects. The genetic basis is largely unknown except for rare variants in several genes. Many candidate genes have been suggested by mouse models and human studies. The purpose of this study was to narrow down the number of candidate genes. METHODS: Whole exome sequencing was performed on 111 unrelated individuals with MRKH; variant analysis focused on 72 genes suggested by mouse models, human studies of physiological candidates, or located near translocation breakpoints in t(3;16). Candidate variants (CV) predicted to be deleterious were confirmed by Sanger sequencing. RESULTS: Sanger sequencing verified 54 heterozygous CV from genes identified through mouse (13 CV in 6 genes), human (22 CV in seven genes), and translocation breakpoint (19 CV in 11 genes) studies. Twelve patients had ≥ 2 CVs, including four patients with two variants in the same gene. One likely digenic combination of LAMC1 and MMP14 was identified. CONCLUSION: We narrowed 72 candidate genes to 10 genes that appear more likely implicated. These candidate genes will require further investigation to elucidate their role in the development of MRKH.

Twenty-year follow-up of the facial phenotype of Brazilian patients with Sotos syndrome.

Sotos syndrome is characterized by overgrowth starting before birth through childhood with intellectual disability and craniofacial anomalies. The majority of patients are large for gestational age with developmental delay or intellectual disability. The majority of cases are caused by pathogenic variants in NSD1. The most consistent physical features in this disorder are facial dysmorphisms including prominent forehead, downslanted palpebral fissures, prognathism with a pointed chin, and a long and narrow face. We present a follow-up to a cohort of 11 individuals found to harbor heterozygous, pathogenic, or likely pathogenic variants in NSD1. We analyzed the facial dysmorphisms and the condition using retrospective over 20 years. Among these patients, followed in our medical genetics outpatient clinic for variable periods of time, all had a phenotype compatible with the characteristic Sotos syndrome facial features, which evolved with time and became superimposed with natural aging modifications. We present here a long-term follow-up of facial features of Brazilian patients with molecularly confirmed Sotos syndrome. In this largest Brazilian cohort of molecularly confirmed patients with Sotos syndrome to date, we provide a careful description of the facial phenotype, which becomes less pronounced with aging and possibly more difficult to recognize in adults. These results may have broad clinical implications for diagnosis and add to the global clinical delineation of this condition.

Associations of gestational cardiovascular health with pregnancy outcomes: the Hyperglycemia and Adverse Pregnancy Outcome study.

BACKGROUND: The American Heart Association's formal characterization of cardiovascular health combines several metrics in a health-oriented, rather than disease-oriented, framework. Although cardiovascular health assessment during pregnancy has been recommended, its significance for pregnancy outcomes is unknown. OBJECTIVE: The purpose of this study was to examine the association of gestational cardiovascular health-formally characterized by a combination of 5 metrics-with adverse maternal and newborn outcomes. STUDY DESIGN: We analyzed data from the Hyperglycemia and Adverse Pregnancy Outcome study, including 2304 mother-newborn dyads from 6 countries. Maternal cardiovascular health was defined by the combination of the following 5 metrics measured at a mean of 28 (24-32) weeks' gestation: body mass index, blood pressure, lipids, glucose, and smoking. Levels of each metric were categorized using pregnancy guidelines, and the total cardiovascular health was scored (0-10 points, where 10 was the most favorable). Cord blood was collected at delivery, newborn anthropometrics were measured within 72 hours, and medical records were abstracted for obstetrical outcomes. Modified Poisson and multinomial logistic regression were used to test the associations of gestational cardiovascular health with pregnancy outcomes, adjusted for center and maternal and newborn characteristics. RESULTS: The average age of women at study exam was 29.6 years old, and they delivered at a mean gestational age of 39.8 weeks. The mean total gestational cardiovascular health score was 8.6 (of 10); 36.3% had all ideal metrics and 7.5% had 2+ poor metrics. In fully adjusted models, each 1 point higher (more favorable) cardiovascular health score was associated with lower risks for preeclampsia (relative risk, 0.67 [95% confidence interval, 0.61-0.73]), unplanned primary cesarean delivery (0.88 [0.82-0.95]), newborn birthweight >90th percentile (0.81 [0.75-0.87]), sum of skinfolds >90th percentile (0.84 [0.77-0.92]), and insulin sensitivity <10th percentile (0.83 [0.77-0.90]). Cardiovascular health categories demonstrated graded associations with outcomes; for example, relative risks (95% confidence intervals) for preeclampsia were 3.13 (1.39-7.06), 5.34 (2.44-11.70), and 9.30 (3.95-21.86) for women with ≥1 intermediate, 1 poor, or ≥2 poor (vs all ideal) metrics, respectively. CONCLUSION: More favorable cardiovascular health at 24 to 32 weeks' gestation was associated with lower risks for several adverse pregnancy outcomes in a multinational cohort.

Nesfatin-1-like peptide is a negative regulator of cardiovascular functions in zebrafish and goldfish.

Nucleobindins (NUCB1 and NUCB2) were originally identified as calcium and DNA binding proteins. Nesfatin-1 (NEFA/nucleobindin-2-Encoded Satiety and Fat-Influencing proteiN-1) is an 82 amino acid anorexigenic peptide encoded in the N-terminal region of NUCB2. We have shown that nesfatin-1 is a cardiosuppressor in zebrafish. Both NUCB1 and NUCB2 possess a -very highly conserved bioactive core. It was found that a nesfatin-1-like peptide (NLP) encoded in NUCB1 suppresses food intake in fish. In this research, we investigated whether NLP has nesfatin-1-like effects on cardiovascular functions. NUCB1/NLP-like immunoreactivity was found in the atrium and ventricle of the heart and skeletal muscle of zebrafish. Intraperitoneal injection (IP) of either zebrafish NLP or rat NLP suppressed cardiac functions in both zebrafish and goldfish. Irisin and RyR1b mRNA expression was downregulated by NLP in zebrafish cardiac and skeletal muscles. However, cardiac ATP2a2 mRNA expression was elevated after NLP injection. Administration of scrambled NLP did not affect irisin, RyR1b or ATP2a2 mRNA expression in zebrafish. Together, these results implicate NLP as a suppressor of cardiovascular physiology in zebrafish and goldfish.

The sympathetic/beta-adrenergic pathway mediates irisin regulation of cardiac functions in zebrafish.

Irisin is a 23 kDa myokine encoded in its precursor, fibronectin type III domain containing 5 (FNDC5). The exercise-induced increase in the expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1-α) promotes FNDC5 mRNA, followed by the proteolytic cleavage of FNDC5 to release irisin from the skeletal or cardiac muscle into the blood. Irisin is abundantly expressed in skeletal and cardiac muscle and plays an important role in feeding, modulates appetite regulatory peptides, and regulates cardiovascular functions in zebrafish. In order to determine the potential mechanisms of acute irisin effects, in this research, we explored whether adrenergic or muscarinic pathways mediate the cardiovascular effects of irisin. Propranolol (100 ng/g B·W) alone modulated cardiac functions, and when injected in combination with irisin (0.1 ng/g B·W) attenuated the effects of irisin in regulating cardiovascular functions in zebrafish at 15 min post-injection. Atropine (100 ng/g B·W) modulated cardiovascular physiology in the absence of irisin, while it was ineffective in influencing irisin-induced effects on cardiovascular functions in zebrafish. At 1 h post-injection, irisin downregulated PGC-1 alpha mRNA, myostatin-a and myostatin-b mRNA expression in zebrafish heart and skeletal muscle. Propranolol alone had no effect on the expression of these mRNAs in zebrafish and did not alter the irisin-induced changes in expression. At 1 h post-injection, irisin siRNA downregulated PGC-1 alpha, troponin C and troponin T2D mRNA expression, while upregulating myostatin a and b mRNA expression in zebrafish heart and skeletal muscle. Atropine alone had no effects on mRNA expression, and was unable to alter effects on mRNA expression of siRNA. Overall, this research identified a role for the sympathetic/beta-adrenergic pathway in regulating irisin effects on cardiovascular physiology and cardiac gene expression in zebrafish.

Glycemic, insulinemic and methylglyoxal postprandial responses to starches alone or in whole diets in dogs versus cats: Relating the concept of glycemic index to metabolic responses and gene expression.

Species differences between domestic cats (Felis catus) and dogs (Canis familiaris) has led to differences in their ability to digest, absorb and metabolize carbohydrates through poorly characterized mechanisms. The current study aimed to first examine biopsied small intestine, pancreas, liver and skeletal muscle from laboratory beagles and domestic cats for mRNA expression of key enzymes involved in starch digestion (amylase), glucose transport (sodium-dependent SGLTs and -independent glucose transporters, GLUT) and glucose metabolism (hexokinase and glucokinase). Cats had lower mRNA expression of most genes examined in almost all tissues compared to dogs (p < 0.05). Next, postprandial glucose, insulin, methylglyoxal (a toxic glucose metabolite) and d-lactate (metabolite of methylglyoxal) after single feedings of different starch sources were tested in fasted dogs and cats. After feeding pure glucose, peak postprandial blood glucose and methylglyoxal were surprisingly similar between dogs and cats, except cats had a longer time to peak and a greater area under the curve consistent with lower glycolytic enzyme expression. After feeding starches or whole diets to dogs, postprandial glycemic response, glycemic index, insulin, methylglyoxal and d-lactate followed reported glycemic index trends in humans. In contrast, cats showed very low to negligible postprandial glycemic responses and low insulin after feeding different starch sources, but not whole diets, with no relationship to methylglyoxal or d-lactate. Thus, the concept of glycemic index appears valid in dogs, but not cats. Differences in amylase, glucose transporters, and glycolytic enzymes are consistent with species differences in starch and glucose handling between cats and dogs.

Associations of Maternal Cardiovascular Health in Pregnancy With Offspring Cardiovascular Health in Early Adolescence.

Importance: Pregnancy may be a key window to optimize cardiovascular health (CVH) for the mother and influence lifelong CVH for her child. Objective: To examine associations between maternal gestational CVH and offspring CVH. Design, Setting, and Participants: This cohort study used data from the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study (examinations: July 2000-April 2006) and HAPO Follow-Up Study (examinations: February 2013-December 2016). The analyses included 2302 mother-child dyads, comprising 48% of HAPO Follow-Up Study participants, in an ancillary CVH study. Participants were from 9 field centers across the United States, Barbados, United Kingdom, China, Thailand, and Canada. Exposures: Maternal gestational CVH at a target of 28 weeks' gestation, based on 5 metrics: body mass index, blood pressure, total cholesterol level, glucose level, and smoking. Each metric was categorized as ideal, intermediate, or poor using pregnancy guidelines. Total CVH was categorized as follows: all ideal metrics, 1 or more intermediate (but 0 poor) metrics, 1 poor metric, or 2 or more poor metrics. Main Outcomes and Measures: Offspring CVH at ages 10 to 14 years, based on 4 metrics: body mass index, blood pressure, total cholesterol level, and glucose level. Total CVH was categorized as for mothers. Results: Among 2302 dyads, the mean (SD) ages were 29.6 (2.7) years for pregnant mothers and 11.3 (1.1) years for children. During pregnancy, the mean (SD) maternal CVH score was 8.6 (1.4) out of 10. Among pregnant mothers, the prevalence of all ideal metrics was 32.8% (95% CI, 30.6%-35.1%), 31.7% (95% CI, 29.4%-34.0%) for 1 or more intermediate metrics, 29.5% (95% CI, 27.2%-31.7%) for 1 poor metric, and 6.0% (95% CI, 3.8%-8.3%) for 2 or more poor metrics. Among children of mothers with all ideal metrics, the prevalence of all ideal metrics was 42.2% (95% CI, 38.4%-46.2%), 36.7% (95% CI, 32.9%-40.7%) for 1 or more intermediate metrics, 18.4% (95% CI, 14.6%-22.4%) for 1 poor metric, and 2.6% (95% CI, 0%-6.6%) for 2 or more poor metrics. Among children of mothers with 2 or more poor metrics, the prevalence of all ideal metrics was 30.7% (95% CI, 22.0%-40.4%), 28.3% (95% CI, 19.7%-38.1%) for 1 or more intermediate metrics, 30.7% (95% CI, 22.0%-40.4%) for 1 poor metric, and 10.2% (95% CI, 1.6%-20.0%) for 2 or more poor metrics. The adjusted relative risks associated with 1 or more intermediate, 1 poor, and 2 or more poor (vs all ideal) metrics, respectively, in mothers during pregnancy were 1.17 (95% CI, 0.96-1.42), 1.66 (95% CI, 1.39-1.99), and 2.02 (95% CI, 1.55-2.64) for offspring to have 1 poor (vs all ideal) metrics, and the relative risks were 2.15 (95% CI, 1.23-3.75), 3.32 (95% CI,1.96-5.62), and 7.82 (95% CI, 4.12-14.85) for offspring to have 2 or more poor (vs all ideal) metrics. Additional adjustment for categorical birth factors (eg, preeclampsia) did not fully explain these significant associations (eg, relative risk for association between 2 or more poor metrics among mothers during pregnancy and 2 or more poor metrics among offspring after adjustment for an extended set of birth factors, 6.23 [95% CI, 3.03-12.82]). Conclusions and Relevance: In this multinational cohort, better maternal CVH at 28 weeks' gestation was significantly associated with better offspring CVH at ages 10 to 14 years.

Encapsulation of Vitamin E in Yogurt-Based Beverage Emulsions: Influence of Bulk Pasteurization and Chilled Storage on Physicochemical Stability and Starter Culture Viability.

Yogurt is a nutritious food that is regularly consumed in many countries around the world and is widely appreciated for its organoleptic properties. Despite its contribution to human dietary requirements, yogurt in its traditional recipe is a poor source of fat-soluble vitamins. To respond to consumer demands and further increase the nutritional value of this product, this work aimed to fortify yogurt with vitamin E by using emulsification as the method of encapsulation. The effects of thermal processing and chilled storage on the physicochemical stability of the yogurt-based beverage was investigated. Vitamin E was only minorly affected by bulk pasteurization at 63 °C for 30 min and remained stable during storage at 4 °C for 28 days. Fortified samples showed increased in vitro antioxidant activity compared with non-fortified samples. Lactic acid bacterial counts were above the minimum recommended levels (>106 cfu/g) after processing and storage. In conclusion, this work has demonstrated that emulsification can be an effective strategy for developing yogurt-based products fortified with fat soluble vitamins.

Metabolomic and genetic associations with insulin resistance in pregnancy.

AIMS/HYPOTHESIS: Our study aimed to integrate maternal metabolic and genetic data related to insulin sensitivity during pregnancy to provide novel insights into mechanisms underlying pregnancy-induced insulin resistance. METHODS: Fasting and 1 h serum samples were collected from women in the Hyperglycemia and Adverse Pregnancy Outcome study who underwent an OGTT at ∼28 weeks' gestation. We obtained targeted and non-targeted metabolomics and genome-wide association data from 1600 and 4528 mothers, respectively, in four ancestry groups (Northern European, Afro-Caribbean, Mexican American and Thai); 1412 of the women had both metabolomics and genome-wide association data. Insulin sensitivity was calculated using a modified insulin sensitivity index that included fasting and 1 h glucose and C-peptide levels after a 75 g glucose load. RESULTS: Per-metabolite and network analyses across the four ancestries identified numerous metabolites associated with maternal insulin sensitivity before and 1 h after a glucose load, ranging from amino acids and carbohydrates to fatty acids and lipids. Genome-wide association analyses identified 12 genetic variants in the glucokinase regulatory protein gene locus that were significantly associated with maternal insulin sensitivity, including a common functional missense mutation, rs1260326 (ß = -0.2004, p = 4.67 × 10-12 in a meta-analysis across the four ancestries). This SNP was also significantly associated with multiple fasting and 1 h metabolites during pregnancy, including fasting and 1 h triacylglycerols and 2-hydroxybutyrate and 1 h lactate, 2-ketoleucine/ketoisoleucine and palmitoleic acid. Mediation analysis suggested that 1 h palmitoleic acid contributes, in part, to the association of rs1260326 with maternal insulin sensitivity, explaining 13.7% (95% CI 4.0%, 23.3%) of the total effect. CONCLUSIONS/INTERPRETATION: The present study demonstrates commonalities between metabolites and genetic variants associated with insulin sensitivity in the gravid and non-gravid states and provides insights into mechanisms underlying pregnancy-induced insulin resistance. Graphical abstract.

Comparison of intestinal glucose flux and electrogenic current demonstrates two absorptive pathways in pig and one in Nile tilapia and rainbow trout.

The mucosal-to-serosal flux of 14C 3-O-methyl-d-glucose was compared against the electrogenic transport of d-glucose across ex vivo intestinal segments of Nile tilapia, rainbow trout, and pig in Ussing chambers. The difference in affinities (Km "fingerprints") between pig flux and electrogenic transport of glucose, and the absence of this difference in tilapia and trout, suggest two absorptive pathways in the pig and one in the fish species examined. More specifically, the total mucosal-to-serosal flux revealed a super high-affinity, high-capacity (sHa/Hc) total glucose transport system in tilapia; a super high-affinity, low-capacity (sHa/Lc) total glucose transport system in trout and a low-affinity, low-capacity (La/Lc) total glucose transport system in pig. Comparatively, electrogenic glucose absorption revealed similar Km in both fish species, with a super high-affinity, high capacity (sHa/Hc) system in tilapia; a super high-affinity/super low-capacity (sHa/sLc) system in trout; but a different Km fingerprint in the pig, with a high-affinity, low-capacity (Ha/Lc) system. This was supported by different responses to inhibitors of sodium-dependent glucose transporters (SGLTs) and glucose transporter type 2 (GLUT2) administered on the apical side between species. More specifically, tilapia flux was inhibited by SGLT inhibitors, but not the GLUT2 inhibitor, whereas trout lacked response to inhibitors. In contrast, the pig responded to inhibition by both SGLT and GLUT2 inhibitors with a higher expression of GLUT2. Altogether, it would appear that two pathways are working together in the pig, allowing it to have continued absorption at high glucose concentrations, whereas this is not present in both tilapia and trout.

Diagnostic prediction model development using data from dried blood spot proteomics and a digital mental health assessment to identify major depressive disorder among individuals presenting with low mood.

With less than half of patients with major depressive disorder (MDD) correctly diagnosed within the primary care setting, there is a clinical need to develop an objective and readily accessible test to enable earlier and more accurate diagnosis. The aim of this study was to develop diagnostic prediction models to identify MDD patients among individuals presenting with subclinical low mood, based on data from dried blood spot (DBS) proteomics (194 peptides representing 115 proteins) and a novel digital mental health assessment (102 sociodemographic, clinical and personality characteristics). To this end, we investigated 130 low mood controls, 53 currently depressed individuals with an existing MDD diagnosis (established current MDD), 40 currently depressed individuals with a new MDD diagnosis (new current MDD), and 72 currently not depressed individuals with an existing MDD diagnosis (established non-current MDD). A repeated nested cross-validation approach was used to evaluate variation in model selection and ensure model reproducibility. Prediction models that were trained to differentiate between established current MDD patients and low mood controls (AUC = 0.94 ± 0.01) demonstrated a good predictive performance when extrapolated to differentiate between new current MDD patients and low mood controls (AUC = 0.80 ± 0.01), as well as between established non-current MDD patients and low mood controls (AUC = 0.79 ± 0.01). Importantly, we identified DBS proteins A1AG1, A2GL, AL1A1, APOE and CFAH as important predictors of MDD, indicative of immune system dysregulation; as well as poor self-rated mental health, BMI, reduced daily experiences of positive emotions, and tender-mindedness. Despite the need for further validation, our preliminary findings demonstrate the potential of such prediction models to be used as a diagnostic aid for detecting MDD in clinical practice.

Maternal metabolites during pregnancy are associated with newborn outcomes and hyperinsulinaemia across ancestries.

AIMS/HYPOTHESIS: We aimed to determine the association of maternal metabolites with newborn adiposity and hyperinsulinaemia in a multi-ethnic cohort of mother-newborn dyads. METHODS: Targeted and non-targeted metabolomics assays were performed on fasting and 1 h serum samples from a total of 1600 mothers in four ancestry groups (Northern European, Afro-Caribbean, Mexican American and Thai) who participated in the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study, underwent an OGTT at ~28 weeks gestation and whose newborns had anthropometric measurements at birth. RESULTS: In this observational study, meta-analyses demonstrated significant associations of maternal fasting and 1 h metabolites with birthweight, cord C-peptide and/or sum of skinfolds across ancestry groups. In particular, maternal fasting triacylglycerols were associated with newborn sum of skinfolds. At 1 h, several amino acids, fatty acids and lipid metabolites were associated with one or more newborn outcomes. Network analyses revealed clusters of fasting acylcarnitines, amino acids, lipids and fatty acid metabolites associated with cord C-peptide and sum of skinfolds, with the addition of branched-chain and aromatic amino acids at 1 h. CONCLUSIONS/INTERPRETATION: The maternal metabolome during pregnancy is associated with newborn outcomes. Maternal levels of amino acids, acylcarnitines, lipids and fatty acids and their metabolites during pregnancy relate to fetal growth, adiposity and cord C-peptide, independent of maternal BMI and blood glucose levels.

Maternal glucose levels during pregnancy and childhood adiposity in the Hyperglycemia and Adverse Pregnancy Outcome Follow-up Study.

AIMS/HYPOTHESIS: Maternal type 2 diabetes during pregnancy and gestational diabetes are associated with childhood adiposity; however, associations of lower maternal glucose levels during pregnancy with childhood adiposity, independent of maternal BMI, remain less clear. The objective was to examine associations of maternal glucose levels during pregnancy with childhood adiposity in the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) cohort. METHODS: The HAPO Study was an observational epidemiological international multi-ethnic investigation that established strong associations of glucose levels during pregnancy with multiple adverse perinatal outcomes. The HAPO Follow-up Study (HAPO FUS) included 4832 children from ten HAPO centres whose mothers had a 75 g OGTT at ~28 weeks gestation 10-14 years earlier, with glucose values blinded to participants and clinical caregivers. The primary outcome was child adiposity, including: (1) being overweight/obese according to sex- and age-specific cut-offs based on the International Obesity Task Force (IOTF) criteria; (2) IOTF-defined obesity only; and (3) measurements >85th percentile for sum of skinfolds, waist circumference and per cent body fat. Primary predictors were maternal OGTT and HbA1c values during pregnancy. RESULTS: Fully adjusted models that included maternal BMI at pregnancy OGTT indicated positive associations between maternal glucose predictors and child adiposity outcomes. For one SD difference in pregnancy glucose and HbA1c measures, ORs for each child adiposity outcome were in the range of 1.05-1.16 for maternal fasting glucose, 1.11-1.19 for 1 h glucose, 1.09-1.21 for 2 h glucose and 1.12-1.21 for HbA1c. Associations were significant, except for associations of maternal fasting glucose with offspring being overweight/obese or having waist circumference >85th percentile. Linearity was confirmed in all adjusted models. Exploratory sex-specific analyses indicated generally consistent associations for boys and girls. CONCLUSIONS/INTERPRETATION: Exposure to higher levels of glucose in utero is independently associated with childhood adiposity, including being overweight/obese, obesity, skinfold thickness, per cent body fat and waist circumference. Glucose levels less than those diagnostic of diabetes are associated with greater childhood adiposity; this may have implications for long-term metabolic health.